Learning outcomes:
1.
The purpose of these labs is to develop knowledge and understanding of pharmacokinetics, and the effect that route of administration has on drug availability.
2.
After you have completed this section you should be able to: a.
Represent graphically plasma drug concentration versus time curve after an oral administration of a drug b.
To calculate the pharmacokinetic parameters from an oral profile, making use of the method of residuals.
Example:
The pharmacokinetics of a potential antiepileptic drug, PEMA were studied following oral administration of 500 mg. The following table lists the resultant plasma concentrations in one subject.
Time (hr) 0.2 0.5
Cp (mg/L) 0.2
0.5
1 1.5 2 3 4 6 10 14 18
3 4.2
4.3
3.8
3.1
2.2
1.1
0.56
0.3
a) Plot the data on semi-log graph paper. b) From a semi-log plot of the plasma concentrations, estimate the elimination half-life of PEMA in this subject. c) Calculate K el
(0.693/T½ ) d) Extrapolate the linear (elimination) portion of the oral curve back to the Y axis and estimate Z (the concentration at time 0 of the extrapolated line). e) Use the method of residuals to draw the ‘apparent’ or residual line, and from this line calculate the T½ of absorption and the K absorption
(K ab
). f) Calculate the total AUC following iv and oral administration; use the equations.
AUC iv
= C
0
/K el
AUC oral
= Z/K el
- Z/K ab g) From the data, estimate the clearance and volume of distribution of PEMA. h) From the Vd data state where the drug distributes to. i) Calculate the oral bioavailability of the drug. j) From the plot of the oral dose, calculate the peak concentration and the time to peak concentration.

Solution: a) Plot the data on semi-log graph paper. See completed graph overleaf b) From a semi-log plot of the plasma concentrations, estimate the elimination half-life of PEMA in this subject.
T
1/2(el)
= 9 h – 4.5 h (see graph) = 4.5 h c) Calculate K el (0.693/T½ ): K el
= 0.693/4.5 = 0.154 h -1 d) Extrapolate the linear (elimination) portion of the oral curve back to the Y axis and estimate Z (the concentration at time 0 of the extrapolated line).
See Graph for plot of the oral concentrations and extrapolation of the line.
Z= 6.2 mg/L

10
1
0.1
0 2 4 6 8 10 12 14 16 18 20
Graph 1 Oral Semi-log plot

Time
0 e) Use the method of residuals to draw the ‘apparent’ or residual line, and from this line calculate the T½ of absorption and the Kabsorption (Kab).
Method of residuals:
Cp
0
Projected (Cp*)
6.2
Apparent (Cp*-Cp)
6.2
0.2
0.5
1
0.2
0.5
3
6.0
5.9
5.5
5.8
5.3
2.3
1.5
2
4.2
4.3
5
4.4
3 3.8 3.8
See Graph 2 for ‘apparent’ line.
At conc 2 mg/L T= 1.1 h
At conc 1 mg/L T = 1.7 h
T½
(abs)
= 0.6 h
K ab
= 0.693/T½ = 0.693/0.6 = 1.155 h -1
0.7
0.1
-

10
1
0.1
0 2 4 6 8 10 12 14 16 18 20
Graph 2 showing ‘apparent’ line for calculating half-life of absorbance.

f) Calculate the total AUC following iv and oral administration; use the equations. g) AUC iv = C
0
/Kel
When the same drug dose was given IV the following data were obtained:
C
0
K el
= 8.3 mg/L
= 0.154 h-1
Equation for AUCiv = C
0
/K el
AUC = 8.3 /0.154 = = 53.9
AUC iv = 54 mg.h.L
-1 h) AUCoral = Z/K el
- Z/K ab
Equation for AUC oral: = AUC0-infinity = Z/K el
- Z/K ab
, where Z is the concentration at which the extrapolated line hits the Y axis.
Z = 6.2 mg/L
K el
K ab
= 0.154 h
= 1.155 h
-1
-1
AUC oral = 6.2/0.154 – 6.2/1.155
= 40.259 – 5.36
= 34.899
~ 35 mg.h.L
-1 i) From the data, estimate the clearance and volume of distribution of
PEMA.
Cl = Dose/AUCiv
= 500mg/54 mg.h.L
-1
= 9.259 L.h
-1
=9.3 L.h
-1 j) From the Vd data state where the drug distributes to.
Vd = Cl/k el
Kel = 0.154 h
Vd = 9.3 L.hr
-1
-1 /0.154 hr -1
= 60.04 L
60 litres is a little more than the total body water, so it distributes throughout the body with a small amount concentrated in tissues; we cannot say which tissues as we do not have the fat:water partition coefficient value

k) Calculate the oral bioavailability of the drug.
F = AUC oral
/AUC i.v.
= 35/54
= 0.648 or 65% l) From the plot of the oral dose, calculate the peak concentration and the time to peak concentration.
Peak concentration is 4.3 mg/L
Time to peak concentration is 2 h

In evaluating different dosage forms of procainamide (a drug introduced to treat arrhythmia of the heart), the following data were obtained.
Route i.v.
Oral: formulation 1
Oral: formulation 2
Dose (mg)
500
1000
1000
AUC (mg.hr/L)
13.1
20.9
19.9
1.
Estimate the bioavailability (F) of the two oral formulations.
F = AUC
Oral
AUC
IV
2.
Calculate the relative bioavailability of formulation 2.
F
1
= Dose
1
F
2
Dose
2
x AUC
2
x AUC
1
3.
Why is the bioavailability of a drug reduced when it is given orally, as compared to an intravenous dose?
4.
Explain the term bioequivalence.

1
2
5
10
200 mg of a drug was given orally to a patient and the following plasma concentrations were recorded:
Time
(h)
Cp
(
 g/ml)
1
0.54
2
1.85
5
3.40
10
3.85
15
3.40
20
3.0
30
1.8
40
1.05
50
0.75
(a) Plot Cp versus time on semi-log paper.
(b) From the terminal (straight line) portion of the curve, calculate the half-life of elimination (t
1/2
) and the elimination rate constant (k el
).
Ans: T1/2 = 23 h
Kel = 0.693/23 = 0.0301 h -1
(c) From the initial rise, calculate the half-life of absorption and the absorption rate constant (kab). Do this by the method of residuals:
 Extend the log-linear portion of the graph to time zero.
 List the values on this "new" line at each of the time points from zero time.
These are known as the projected values. They represent the values that would be obtained if the drug was given by the i.v. method.
 Subtract the real measured plasma concentrations from each of these projected values. These values are known as the apparent values. They represent the difference between i.v. and oral methods of drug administration, and hence provide information pertaining to absorption.
 Plot these apparent values on the same semilog plot and draw a straight line through the points.
 From this line, calculate the half-life of absorption and kab.
Time
0
Cp
0
Projected (Cp*)
7.5
Apparent (Cp*-Cp)
7.5
0.54
1.85
3.40
3.85 3.85 -

(d) Calculate AUC
AUC
0-infinity
= Z/kel - Z/kab
Z = 7.5 mg/L
(e) From the graph: Estimate the peak concentration
(f) Estimate the time to peak concentration
(g) Calculate the clearance, given that the bioavailability of the drug is 70% (0.7).
Cl = F x dose/AUC oral
(h) What is the volume of distribution?
(i) Based on the volume of distribution, where does the drug distribute to?